Abstract Parkinson's disease is characterized by the degeneration of dopamine-generating neurons in the motor control pathways of the brain. While pharmacological therapies can effectively treat symptoms of the disease, they do not slow continued neurodegeneration. Indeed, disease-modifying therapies represent one of the great unmet needs in Parkinson's disease treatments. Toward this end, gene therapy holds promise to treat the root cause of many pathologies of the central nervous system, including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracellular matrix, which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact ?brain penetrating? nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to extracellular matrix components. Furthermore, we showed that this combined approach could be used to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate robust, localized, and sustained transgene expression without signs of toxicity or astrocyte activation. Moreover, preliminary results demonstrate the potential for delivering therapeutic genes to restore dopaminergic neurons and motor function in a rat model of Parkinson's disease. Our long-term goal, then, is to develop non-invasive and targeted gene therapy strategies that effectively reverse PD neurodegeneration via the delivery of neurotrophic gene vector nanoparticles into the brain. First, in order to improve delivery efficiency in the brain, we will deliver two state-of-the-art DNA-BPN polymer formulations including polyethylenimine (PEI) and poly (?- amino ester) (PBAE) with FUS. We will then complex the highest efficiency formulation with a plasmid expressing the therapeutic GDNF gene and deliver it to the striatum of a Parkinsonian rat. Improvements in motor function and dopaminergic neuron morphology will be assessed with behavioral assessment as well as with molecular indicators of dopaminergic function and neuronal morphology. We predict that image-guided delivery of therapeutic DNA-BPN with FUS will constitute a safe and non-invasive strategy for targeted gene therapy to the brain and restore dopaminergic neurons and improve motor function in a rat model of Parkinson's disease.